Project Summary COPD is a common and serious disease with no cure that is characterized by chronic, progressive lung damage, a decline in pulmonary function and quality of life, and often death. The two major clinical features of COPD are emphysema and chronic bronchitis. COPD is mainly associated with exposure to cigarette smoke (CS), however, about 3% of COPD patients have a genetic deficiency of alpha-1 antitrypsin (AATD). AATD patients represent an orphan disease population for which emphysema is the primary cause of death, and is a relatively homogenous group with a more efficient and less costly clinical development path compared to the broad COPD population. Allinaire Therapeutics, LLC, has demonstrated that EMAP II (endothelial monocyte-activating protein) is a novel therapeutic target for emphysematous COPD that plays a central role in driving the underlying pathology of the disease, including lung inflammation and alveolar destruction. EMAP II levels in the lungs of patients positively correlate with the severity of COPD and remain elevated even after smoking cessation. Furthermore, lung-specific overexpression of EMAP II induces emphysematous changes in mice, and a tool rat antibody to EMAP II (M7/1) blocks the progression of chronic CS-induced lung emphysema in mice. Work supported by the phase 1 SBIR grant resulted in the synthesis of fully humanized versions of the rat M7/1 mAb. Several leads were identified with appropriate potency and developability properties to be considered for optimization. In addition, preliminary data presented in the application demonstrates that treatment with one of the humanized EMAP II mAbs prevented lung macrophage infiltration in a sub-chronic (4 week) CS-exposure model. The specific aims of this Phase II research plan are: Aim 1. Selection of an optimized, high-affinity EMAP II mAb development candidate. The most potent of the 4 current leads will be identified (by SPR) and used to perform lead optimization, affinity maturation, and stable cell line development to produce a clinical candidate with sub-nanomolar affinity and suitable manufacturability properties; Aim. 2 In vivo testing of the lead mAb in a chronic CS-exposure model of emphysema in mouse. The dose-response effects of the clinical development candidate mAb will be tested in a model of chronic CS exposure to confirm a reduction in emphysema endpoints. The mAb will be administered therapeutically via the clinically relevant subcutaneous route; Aim 3. Target validation for EMAP II in AATD patient samples, mouse elastase model, and human lung cells. Serum EMAP II will be measured in individuals with COPD of different severities with or without AATD to determine the correlation between EMAP II and disease severity. Further target validation of EMAP II in the context of AATD will be determined by testing the effects of the mAb in the mouse model of elastase- induced emphysema and human lung cells. Completion of the Phase II milestones will provide Allinaire with a strong pre-clinical data package to enable either partnering of the project with a Pharmaceutical company or additional fund-raising to support progression of the project to manufacturing and IND-enabling studies, as critical steps towards clinical trials with an EMAP II mAb in AATD patients initially, and subsequently in the broader COPD population with emphysema.